Common variable immunodeficiency (CVID) is a clinical diagnosis given to patients who suffer with unexplained deficiencies of serum immunoglobulins. Most CVID patients present with recurrent sinopulmonary infections. Among our clinic population, the greatest genetic linkage is to the major histocompatibility complex (MHC) on chromosome 6, with more than 80% of our patients inheriting either HLA*B08 or HLA*B44. We recently characterized a separate group of clinic patients who presented with adult-onset recurrent sinopulmonary infections (RESPI) and serum immunoglobulin levels above the threshold for diagnosis with CVID, but with the same distribution of HLA*B08 and HLA*B44 as that seen in CVID. Recognition of RESPI patients among first and second degree relatives of CVID patients, including two identical twins discordant for RESPI and CVID, led us to the hypothesis that RESPI patients are suffering from the effects of the same genetic susceptibility to immune dysfunction that manifests more severely in classic CVID. Careful analysis has shown a variety of abnormalities in either the number or function of a number of different lymphocyte subsets in both RESPI and CVID patients. For example, NK cells have been reported to be depressed in number, but the role of factors that can mediate NK cell function, including the role of KIR and MHC ligands, remains unknown. We propose to use our population of RESPI/CVID patients to map the putative common susceptibility gene for RESPI/CVID within the MHC, to characterize HLA/KIR interactions, and to evaluate the expressed B cell and T cell antigen receptor repertoires in these patients. This comprehensive analysis of the MHC, KIR, BCR and TCR could help define and extend the spectrum of what is already the most common primary immune deficiency under the care of clinical immunologists in the US, as well as to elucidate the mechanism(s) that underlie susceptibility to infection, facilitate diagnosis, and point to new avenues for prevention and treatment.